Currently, 23 US states and DC have legalized the use of marijuana as a medical treatment. Maryland, Minnesota and New York are the most recent to join in 2014, and legislation to legalize medical marijuana in Florida, Ohio and Pennsylvania is pending. With policy changing rapidly on the medical applications of the drug on a state-by-state basis, we take a look at where the debate stands concerning the available evidence on medical marijuana and its implementation as a therapy.

The fight by pro-medical marijuana groups, patients and doctors to have the drug recognized as a valid treatment for specific medical conditions has been a long one. In 1972, the National Organization for the Reform of Marijuana Laws (NORML) filed the first petition to have marijuana rescheduled from a Schedule 1 to Schedule 2 drug, so that it could be legally prescribed by physicians.

The petition followed President Richard Nixon's declaration of a "war on drugs," in which he rejected the recommendations of a White House commission that had voted to legalize marijuana, stating that:

"I am against legalizing marijuana. Even if the Commission does recommend that it be legalized, I will not follow that recommendation [...] I can see no social or moral justification whatever for legalizing marijuana. I think it would be exactly the wrong step. It would simply encourage more and more of our young people to start down the long, dismal road that leads to hard drugs and eventually self-destruction."

NORML's petition, therefore, was met with great resistance. In 1970, Nixon's Controlled Substances Act had classified marijuana as a drug with "no accepted medical use," and it was this act that led to the creation of the Drug Enforcement Administration (DEA) - a body charged with enforcing federal drug laws - in 1973.

In 1996, California had become the first state to legalize marijuana for medical applications.

The DEA refused to process NORML's petition, leading to a still-ongoing series of controversial legal battles between the DEA and campaigners throughout the federal court system. A sequence of legal hurdles led to the DEA delaying the final decision on NORML's proposed rescheduling for 16 years.

A subsequent petition in 1995 was held in similar legal limbo for 5 years, and a third petition took 9 years to be processed. In two of these cases, it required multiple lawsuits to force the agency to act.

Meanwhile, in 1996, California had become the first state to legalize marijuana for medical applications. Under Proposition 215, patients and primary caregivers were allowed to possess and cultivate marijuana for the treatment of illnesses - such as AIDS, cancer, muscular spasticity and migraines - if they had a physician's recommendation.

Although the following decade would see the legalization of medical marijuana gradually spread to states such as Alaska, Oregon, Washington, Maine, Hawaii, Colorado and Nevada, a flurry of political activity in recent years has seen legalization become a pressing national issue. And, as ever, the relationship between science and legislation on the issue has been a complex and often uneasy one.

What science has prompted legislative rethink?

Research by the scientists Allyn Howlett and William Devane in 1988 proved the existence of a cannabinoid receptor in the rat brain. This led to Miles Herkenham, senior investigator at the National Institute of Mental Health (NIMH), discovering the cannabinoid system in humans in 1990.

This research was considered to be highly significant because it offered a scientific basis for explaining how pharmacological effects of marijuana might occur when cannabinoids - 66 naturally occurring compounds found in marijuana - bind with the cannabinoid receptors in the brain.

In 1992, a team led by Dr. Raphael Mechoulam discovered the endocannabinoid system in humans - the brain's own naturally occurring equivalent to the cannabinoids found in marijuana; lipids that bind with our cannabinoid receptors in the same way that marijuana-derived cannabinoids do, and which produce similar effects.

In the wake of the cannabinoid breakthroughs, the 90s saw a groundswell of support for research into and/or legalization of medical marijuana, with the New England Journal of Medicine calling for federal authorities to "rescind their prohibition of the medicinal use of marijuana."

In 1991, 53% of surveyed oncologists supported making marijuana available by prescription, and in 1993, the American Medical Student Association unanimously endorsed the rescheduling of marijuana.

These events marked a turning point in the US for the medical marijuana debate. Because, although historically medical marijuana dates as far back as 2,900 BC and its use in Chinese medicine, modern science had been reluctant to engage with the topic of marijuana as medicine, with evidence for its beneficial properties being largely anecdotal.

Despite this, in 1985, the Food and Drug Administration (FDA) had approved the drug marinol - a synthetic version of delta-9 tetrahydrocannabinol (THC), the cannabinoid in marijuana that provides the psychotropic "high" - to ease the side effects of chemotherapy in cancer patients.

What conditions can marijuana treat, and where is the evidence for it?

In states where medical marijuana is legal, it is only approved for treating a list of conditions specified in legislation. However, this list of conditions varies from state to state.

Cancer, HIV/AIDS and multiple sclerosis are the most common conditions for which marijuana is approved as a treatment in the US, with evidence from some studies suggesting that marijuana relieves nausea, improves appetite and eases spasms in patients with these serious conditions.

Some physicians are concerned over the lack of reliable evidence to support marijuana as an effective treatment for many conditions.

The inclusion of such a wide-ranging palette of diseases has troubled some physicians, who cite a lack of reliable evidence to support marijuana as an effective treatment for many - if not all - of these conditions.

In a recent New York Times feature, for instance, experts flatly rejected the notion that the drug could be effectively used to treat glaucoma or Alzheimer's. The American Glaucoma Society state marijuana is an "impractical" treatment compared with the standard once-a-day eyedrops.

The intensity of the battleground over marijuana as epilepsy treatment is best surmised by the popular campaign for lawmakers to allow access to "Charlotte's Web" - a strain of marijuana whose particular cannabinoid make-up was reported by Matt and Page Figi of Colorado to have reduced the 300 grand mal seizures a week their daughter Charlotte was experiencing to just two or three per month.

The Times opined, though, that "there is no rigorous scientific evidence that marijuana effectively treats the symptoms of many of the illnesses for which states have authorized its use," arguing that lawmakers have acted on the outcomes of public referendums and "animal studies and heart-wrenching anecdotes," rather than on the evidence of scientists and doctors.

We put this to Kris Hermes, spokesperson for Americans for Safe Access - an organization committed to "advancing legal medical marijuana therapeutics and research."

"To say that studies determining the medical efficacy of marijuana is limited to animal studies and anecdotal stories is flatly false," Hermes replied.

"So, lawmakers are actually responding to scientific studies, which are often brought to their attention by constituents, and are accordingly granting protection to patients who therapeutically benefit from cannabis."

Other pro-marijuana pressure groups - such as the Marijuana Policy Project (MPP) - acknowledge a paucity of the "gold standard" randomized controlled trials that are necessary for determining which drugs are effective in humans and can be approved, but explain that legal obstructions have prevented researchers from conducting these trials.

"Unfortunately, the federal government has been blocking research and human trials that would explore the potential medical benefits of marijuana," MPP spokesperson Morgan Fox told Medical News Today, "but research in other countries, particularly Israel, has been under way for decades.

"In addition, there are numerous non-clinical studies that support the medical efficacy of marijuana, as well as mountains of anecdotal data from the states where medical marijuana laws exist."

Obstructions to marijuana research

One of the most significant obstacles to conducting medical marijuana research in the US lies with obtaining access to the drug. Marijuana is a unique substance in that it is the only drug where access to it for research purposes is controlled by the National Institute on Drug Abuse (NIDA).

This has proved a huge barrier to medical marijuana research. Guidelines issued to NIDA from the Department of Health and Human Services (HSS) on the provision of marijuana to researchers even explicitly state that if the goal of the research is to develop marijuana into an FDA-approved prescription medicine, then NIDA must refuse access to its stock of marijuana plants.

A report by the Drug Policy Alliance outlined the inconsistent logic in these guidelines, given that even cocaine, heroin, methamphetamine, LSD and MDMA are made available by the DEA to private researchers.

Also, while human trials for any Schedule 1 drug require approval from the FDA - which involves a 30-day decision-making deadline - studies specifically involving marijuana must also be routed through NIDA and HSS's own reviews, which have no deadlines and no appeals process.

"Lawmakers seem overly concerned with people who use marijuana to treat their conditions also feeling good while doing so," says Morgan Fox.

The Drug Policy Alliance note that even when marijuana research is approved, the quality of the sole strain supplied by NIDA is ineffective for research purposes, given that its THC content is less than three times as potent as much of the marijuana used by patients in states where it is legal.

The legal wrangles surrounding obtaining marijuana for research purposes is perhaps best typified by the 12-year legal campaign of Prof. Lyle Craker, director of the University of Massachusetts-Amherst's Medicinal Plant Program, who sought to obtain a license from the DEA to establish a facility for producing research-grade marijuana for FDA-approved studies.

Despite the DEA's own Administrative Law Judge ruling in the Craker's favor, the request was stalled for 12 years before it was definitively over-ruled by DEA Administrator Michele Leonhart.
Leonhart's action came just days before the inauguration of President Obama, who had publicly endorsed the legalization of medical marijuana.

'A catch-22'

"Any time there is suppression of data generation - as was the case during prohibition - it will take time to generate the data to fill the void. We can't generate data without legalization and good policymaking is dependent on data - a catch-22."

For now, it may be possible that - by reacting to the demands of popular consensus - policy may have leapt ahead of research, which is still entangled in the red tape of a Nixon-era "war on drugs" policy.

Evidence of this is shown by the lack of quality guidelines offered by states as part of their legalization legislation and policies. Currently, it is a free-for-all, with only commercial enterprises such as MCR Labs offering testing services for patients and guidance on which strains of marijuana may be most effective for their particular condition.

As each combination of the 66 cannabinoids identified in medical marijuana is associated with different perceived medical benefits - and with the make-up of each strain varying wildly from batch to batch - defining and enforcing measurable quality standards would appear to be paramount.

Without them, medical marijuana risks appearing a modern "cure-all snake oil," but identifying these standards is not possible without research access to a variety of strains of the drug.

Instead, it seems lawmakers are less worried about the health implications of cannabinoid variations, and more concerned with minimizing patient exposure to THC - the compound responsible for the "high" loved by recreational users of the drug. Tellingly, the only forthcoming chemistry guidelines for medical marijuana proposed by the Department of Public Health are on the maximum allowed levels of THC.

MPP's Morgan Fox told us:

"Despite the fact that marijuana is objectively safer than many prescription drugs which cause euphoria, impairment, or some sort of 'high,' lawmakers seem overly concerned with people who use marijuana to treat their conditions also feeling good while doing so. This is most likely to appease political opponents and to seem 'tough on drugs,' but unfortunately results in laws that interfere with physicians and medical marijuana innovators, and leaves most patients behind."

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